Abstract Bladder pain and dysfunction are sources of profound debilitation for millions of people in the United States with interstitial cystitis/bladder pain syndrome, overactive bladder, and neurogenic bladder. Current treatments for these disorders are ineffective and do not address the underlying pathology. A substantial barrier to the development of improved therapeutics is an insufficient understanding of mechanisms by which the bladder is controlled. Progress will depend critically on the development of new technologies in neural interfaces. In particular, a combination of optogenetic approaches along with new, wireless optoelectronic systems and electronic hardware for nerve recording and electrical stimulation will provide a unique set of tools for enhanced insights into peripheral organ control. Additionally, the ability to measure, in real-time, neural inflammation and to programmably deliver local anti-inflammatory agents at the neural interface will not only allow robust, high performance chronic integration, but also further the understanding of maintenance at nerve- device interfaces in other applications. In this proposal, we develop a suite of soft, fully-implantable microscale devices with advanced design features specifically configured to minimize and mitigate inflammation for essentially permanent integration with the targeted nerves. In Aim 1, we propose to integrate optogenetic technologies with fully-implantable wireless systems for inhibition of peripheral neurons innervating the bladder. In Aim 2, we propose to integrate ultra-thin, flexible electrode technology and novel neuroinflammatory monitors to the wireless control of bladder peripheral nerves. In Aim 3, we integrate a fully-implantable, wirelessly programmable microfluidic platform for closed-loop maintenance of the chronic nerve interface. Our collaborative team has extensive success merging technologies into unified multi-modal devices and subsequently applying them to the mechanistic study of neuronal subpopulations. The technology produced by these aims will be optimally positioned to study mechanisms of control of end-organ function, and to do so in a way that is minimally invasive.